세미나

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, yet their function is impaired in autoimmune diseases such as rheumatoid arthritis (RA). While most studies have focused on circulating Tregs, the mechanisms governing Treg dysfunction within inflamed tissues remain poorly understood.
Here, we performed single-cell RNA sequencing of Tregs from RA synovial tissue and identified two distinct Treg states with divergent functions. CD25 hi CXCR6 pos Tregs exhibited a highly suppressive phenotype, were clonally expanded, and displayed enhanced glycolytic activity. In contrast, CD25 lo AREG pos Tregs represented a dysfunctional state enriched specifically in synovial tissue, characterized by reduced suppressive capacity and features of incomplete di�erentiation.
Mechanistically, we found that the synovial microenvironment actively shapes these divergent Treg states. Synovial fibroblasts generate active cortisol, which induces AREG expression, suppresses glycolysis, and impairs Treg function, driving the emergence of dysfunctional CD25 lo AREG pos Tregs. In turn, AREG promotes a pro-inflammatory phenotype in synovial fibroblasts, establishing a pathogenic feedback loop. In contrast, macrophagederived membrane-bound TNF supports the di�erentiation and function of CD25 hi CXCR6 pos
Tregs through TNFR2 signaling.
Importantly, TNFR2 engagement restored glycolysis, FOXP3 expression, and suppressive function, and prevented the acquisition of the dysfunctional Treg state. These findings reveal that human Treg fate is dynamically regulated by tissue-specific cues, leading to either maintenance of suppressive function or acquisition of a dysfunctional, pro-inflammatory phenotype.
Together, this study defines a tissue-driven mechanism of Treg dysfunction in human RA and highlights TNFR2 signaling as a potential therapeutic strategy to restore Treg stability in inflammatory diseases.